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Maternal low sodium intake and early postnatal diuretics program metabolic and ventilatory dysfunction in mice

Pediatric Research (2025)Cite this article

Abstract

Background

Perinatal disruption of sodium homeostasis, which is critical for organ and cell function, may impact growth, metabolism, and pulmonary function.

Methods

Two murine models were studied. First, maternal mice were supplied with a standard (0.15%) or low sodium (0.04% Na) diet from embryonic day 18 until postnatal day 21 (E18-P21). Second, offspring of mothers on standard Na were administered daily furosemide (30 mg/kg ip) on P10-P13 or sham injection. All pups received 0.15% Na diet at weaning. In male offspring, weight and body composition were serially measured while total energy expenditure was determined at 8–9 weeks of age. Ventilatory function was assessed at 3–5 weeks and again at 6–8 weeks of age in males and females. Lung structure was assessed at 9–10 weeks.

Results

Maternal low Na diet programmed significantly decreased weight gain in offspring associated with increased total energy expenditure. No significant effects on lung structure or breathing were seen. Furosemide resulted in increased weight, fat and fat-free mass in males. Furosemide was also associated with significantly decreased minute ventilation and tidal volume in males without changes to lung structure.

Conclusion

Perinatal Na homeostasis is crucial for long-term growth, metabolism, and pulmonary function.

Impact

  • Maintenance of early life sodium homeostasis is essential for growth and organ development

  • Using different mouse models, we demonstrated a crucial role of early Na balance in long term growth, body composition, and metabolic and respiratory functions.

  • Optimized intervention to maintain sodium homeostasis may improve long-term outcomes of preterm infants.

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Fig. 1: Timeline of study protocols.
Fig. 2: Effect of maternal diet on body mass and composition of offspring of both sexes.
Fig. 3: Effect of maternal diet on breathing measurements in offspring of both sexes.
Fig. 4: Effect of maternal diet on lung histology in offspring of both sexes.
Fig. 5: Effect of earl life furosemide administration on body mass and composition.
Fig. 6: Effect of early life furosemide administration of breathing measurements.
Fig. 7: Effect of early life furosemide administration on lung histology.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author to researchers who provide a methodologically sound proposal. Data requestors will need to sign a data use agreement approved by the Medical College of Wisconsin.

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Acknowledgements

The authors gratefully acknowledge assistance provided by the Medical College of Wisconsin Comprehensive Rodent Metabolic Phenotyping Core and Biomedical Resource Center. The authors also wish to acknowledge technical support from Kelsey K. Wackman and Ko-Ting Lu. Schematics were made using Biorender.com.

Funding

This work was supported by the NIH grants DK133121, HL134850, the Medical College of Wisconsin Clinical and Translational Science Institute (UL1TR001436), the Children’s Wisconsin Children’s Research Institute, endowments from the Butenhoff and Mellowes families, and the Advancing a Healthier Wisconsin Endowment to the Medical College of Wisconsin.

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Author notes

  1. These authors contributed equally: Alyssa M. Madison, Benjamin R. Araya.

Authors and Affiliations

  1. Departments of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    Alyssa M. Madison, Benjamin R. Araya, Connie C. Grobe & Jeffrey L. Segar

  2. Departments of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA

    Alyssa M. Madison, Justin L. Grobe, Jeffrey L. Segar & Gary C. Mouradian Jr

  3. Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Justin L. Grobe & Gary C. Mouradian Jr

  4. Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Justin L. Grobe, Jeffrey L. Segar & Gary C. Mouradian Jr

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  1. Alyssa M. Madison
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  2. Benjamin R. Araya
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  3. Connie C. Grobe
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  4. Justin L. Grobe
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Contributions

A.M., B.A., J.S., and G.M. conceived the study. A.M., B.A. and C.G. performed the experiments. A.M., B.A., J.G., J.S., and G.M. analyzed the data. J.G. and G. M. provided essential input. A.M, B.A, and J.S. wrote the manuscript. All authors critically reviewed and revised the manuscript and gave their final approval for manuscript submission.

Corresponding author

Correspondence to Jeffrey L. Segar.

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Madison, A.M., Araya, B.R., Grobe, C.C. et al. Maternal low sodium intake and early postnatal diuretics program metabolic and ventilatory dysfunction in mice. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04689-4

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